Biologics Feature

Organoids Set to Dominate Stem Cell Therapy

Biloine W. Young • Fri, June 23rd, 2017

Welcome to the world of organoids—miniature stem cell derived human organs.

According to Don Gibbons, writing for MedPage Today, organoids are expected to become “invaluable tools” for modeling disease, drug screening, toxicity testing, and a wide variety of therapeutic purposes.

Participants at the Boston June 2017 meeting of the International Society for Stem Cell Research learned of organoids generated from pluripotent stem cells.

Hans Clevers, M.D., Ph.D., of Humbrecht Institute in the Netherlands, called the gut stem cell "the champion of all stem cells," in that it replaces the entire intestinal lining of treated rodents every four days as well as seeking out and healing induced lesions. Similarly, gastric organoids have been able to heal Helicobacter-induced lesions in the stomachs of rodents.

First developed about four years ago, organoids have now been made for virtually every organ. Clevers said it is quite easy to source the starting cells. Lung organoids can be grown from sputum, and bladder and kidney organoids can be made from urine.

Organoids generated from adult pluripotent stem cells—usually by reprogramming adult cells from patients to create personalized organoids, or brain organoids, are the most controversial of the new cellular entities.

Researchers noted that patients viewed their mini-organs differently from how they did their stem cells in a dish. Gibbons quoted panelist Marieke Broekman, M.D., Ph.D., of Harvard Medical School, whose patients would declare with some emotion, "That is my mini brain" upon seeing their neural cell organoid.

The use of brain cells to create organoids raises the issue of creating animal/human chimers or more humanized animals. The stem cell field has long dealt with the ethical issues of creating animal/human chimers, particularly involving brain cells, said Insoo Hyun, Ph.D., of Case Western Reserve University in Cleveland. Organoid brain work could result in animals much more humanized than cell-based work, he cautioned.

Speaking from the audience, according to Gibbon’s report was Bernard Siegel, J.D., of the Regenerative Medicine Foundation, who said: "This is a Dolly the sheep moment.” which raised the question, to what extent is creating an organoid creating a person?

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One Molecule Commands Stem Cells: “Build Bone!”

Elizabeth Hofheinz, M.P.H., M.Ed. • Thu, September 22nd, 2016

It turns out, say researchers at the University of California (UC) San Diego, that a molecule occurring naturally in the body can encourage human pluripotent stem cells to regenerate bone tissue. Known as adenosine, the molecule helped repair cranial bone defects in mice without developing tumors or causing infection.

"One of the broader goals of our research is to make regenerative treatments more accessible and clinically relevant by developing easy, efficient and cost-effective ways to engineer human cells and tissues, " said Shyni Varghese, Ph.D., a bioengineering professor at UC San Diego and senior author of the study, in the August 31, 2016 news release.

“Another challenge is producing stem-cell-derived tissues or organs that don't develop teratomas—tumors that contain a variety of tissues found in different organs—when transplanted. Teratomas are what can happen when some of the pluripotent stem cells go rogue and differentiate uncontrollably.”

“Like living bone cells in the body, the resulting osteoblasts built bone tissues with blood vessels. When transplanted into mice with bone defects, the osteoblasts formed new bone tissues in vivo without any signs of teratoma formation.”

Dr. Varghese told OTW, “This work stems from our previous study, which investigated how calcium phosphate minerals found in bone tissue induce stem cells to differentiate into osteoblasts. We have identified that stem cells take up calcium phosphate to produce ATP, a metabolic molecule, which then breaks down into adenosine and functions as an autocrine or paracrine molecule and signals the stem cells to become osteoblasts.

“Our study shows that adenosine can be used to derive large numbers of osteoblasts from hESCs [human embryonic stem cells] and hiPSCs [human induced pluripotent stem cells]. These hESC- and hiPSC-derived osteoblasts contribute to bone tissue formation and treat critical sized bone defects.”

Cartilage Cell Repair System Granted U.S. Patents

Biloine W. Young • Wed, September 18th, 2013

PUR Biologics, LLC announces that it had been granted two patents by the U.S. Patent office covering multipotent stem cell-derived material. The new inventions were developed by PUR to assist physicians with the repair and regeneration of tissue. The office issued the patents to PUR’s joint venture partner, Histogen, Inc. in early September.

The patents describe the very novel Histogen technology for de-differentiation of fibroblast cells into multipotent stem cells by way of low oxygen and special culture conditions. The patent also covers methods of inducing tissue repair and regeneration by contacting cells with the naturally-secreted multipotent cell conditioned media (CCM) and extracellular matrix (ECM) materials.

Histogen’s officials explain that through this now patented process, newborn cells naturally produce the vital proteins and growth factors from which the company has developed its rich product portfolio. Histogen's technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of multipotent human proteins that have been shown to support stem cell growth and differentiation

“These novel multipotent cell-derived materials hold tremendous potential in orthopedic applications, where we seek to regenerate musculoskeletal tissues and support stem cell growth, ” said Ryan Fernan, CEO of PUR Biologics. “Particularly exciting to us is the ability of the material to induce angiogenesis, which is not addressed with currently available orthopedic products.”

Fernan explains that unlike other stem cell-derived therapies, Histogen’s process uniquely begins with newborn fibroblast cells, a safe, well-established and non-controversial cell source, and converts the cells into multipotent stem cells without genetic manipulation. PUR Biologics is currently researching and developing products based upon the CCM and ECM materials produced by these multipotent cells, which have potential benefit in a number of orthopedic applications such as bone and cartilage regeneration.

Burak Ozgur, M.D., chief of Neurosurgery Spine Service at Hoag Hospital, said, “While there is a lot of excitement and promise around stem cell-derived treatments in orthopedics, therapies utilizing embryonic stem cells or genetically manipulated induced pluripotent stem cells carry inherent ethical and potential safety concerns for patients. Products that could capture the benefits of stem cell treatments without these concerns, such as the multipotent cell materials being developed by PUR, hold tremendous potential as the future of orthopedics.”

Japanese Scientists Test Yamanaka’s Work

Biloine Young • Wed, October 31st, 2012

Japanese scientists, while basking in the glow of Shinya Yamanaka’s winning of the Nobel Prize, are rushing to put his work to the test in human trials. Scientists at the Riken Center for Developmental Biology in Kobe plan to use induced pluripotent stem cells (iPS) in a human trial with patients with macular degeneration—a disease in which the retina becomes damaged and patients lose their vision.

Researchers led by Masayo Takahashi at the Riken center plan to apply Yamanaka's technique to the patients' own skin cells to turn them into stem cells before cultivating them to become a certain type of retinal cell. Doctors plan to then transplant those developed retinal cells into the patients' eyes.

The Riken Center will be the first to use Yamanaka’s technology that allows adult stem cells derived from skin to mimic the power of embryonic cells. Major pharmaceutical firms, such as Pfizer, based in New York, are also planning trials of stem cells, but these trials involve cells that are derived from human embryos. Pfizer plans to start a trial of an embryonic stem-cell therapy among patients with macular degeneration next year, according to the U.S. National Institutes of Health's clinicaltrials.gov website. In an interview in London, John B. Gurdon, who shared this year's Nobel Prize with Yamanaka, said "The work in that area looks very encouraging."

Scientists first must ensure that the cells are safe, Yamanaka said in a video appearance from Japan: ‘"We need to double-check we don't see any severe side effects in patients after transfer. That's where we have been spending most of our time." In the case of macular degeneration, he said, “We are getting closer and closer. It’s almost ready to go.”

Genes May Bias Stem Cell Development

Biloine W. Young • Tue, June 18th, 2013

As workers with stem cells know, human cells lines, whether they are embryonic or induced pluripotent, can develop into a wide variety of cells or tissues in the body. Now researchers at Boston Children’s Hospital have discovered that stem cells that express a gene called WNT3 are biased to develop into cell and tissues of the pancreas, liver and bladder. This suggests that other genes may be biomarkers for stem cells with preferences for turning into other tissue types. If so, markers such as this would make it easier for stem cell scientists to choose the right cell line when they want to generate specific tissues.

According to the Boston Children’s press release, Wei Jiang and Yi Zhang, both Ph.D.s, led the study and published their findings in the journal Stem Cell Reports. Zhang said, "If you want to differentiate stem cells into pancreas cells, for instance, you want to start with a line with a high differentiation potential for endoderm. It's like athletes and sports. Some athletes are built for football, some for baseball, and some for swimming. Every cell line has its own strengths, and the challenge is knowing what those strengths are."

Currently, investigators must test several lines with the same differentiation process—which can take a great deal of time and effort—and then use the one that turns out to be the most efficient at producing cells of the type they need. What they would like to be able to do, Zhang says, "is select the most appropriate cell line without having to carry out full differentiation experiments first."

How WNT3 affects endoderm differentiation potential is not yet clear, and is something Zhang wants to understand. But he believes that other genes may possibly serve as markers for selecting lines primed for mesoderm and ectoderm development. "We would like to find other markers and develop a scoring system, " he said. "There are many hESC and iPSC lines, and we need a simple way to tell which to use in order to produce particular cell types."

Hand of God at Work?

Biloine W. Young • Thu, May 30th, 2013

Michael Smith, North American correspondent for MedPage Today, reports that, “for the first time, researchers have efficiently produced human embryonic stem cells, using a process similar to the one that produced the famous cloned sheep, Dolly.” Researchers created embryonic stem cell (ESC) lines using somatic cell nuclei and unfertilized human oocytes.

Smith writes “This is the first time that researchers have efficiently produced human embryonic stem cells”. Shoukhrat Mitalipov, Ph.D., of Oregon Health & Science University in Portland, Oregon and his colleagues, report that cells produced by somatic cell nuclear transfer appeared completely normal and have the potential to develop into a variety of other cell types.

Smith explained that in somatic cell nuclear transfer, the nucleus is taken from a donor cell and transferred to an oocyte, whose own nucleus has been removed. Larry Goldstein, Ph.D., director of the stem cell program at the University of California San Diego, called the process reported by Mitalipov and colleagues as being “stunningly efficient, " requiring only a handful of oocytes. "What these researchers have cracked is a set of manipulations and conditions" that could lead to efficient production of ESCs, both for therapy and research, he added. Writing in the June 6 issue of Cell, Mitalipov stated that stem cell lines could be produced from as few as two human oocytes.

"Our finding offers new ways of generating stem cells for patients with dysfunctional or damaged tissues and organs, " Mitalipov said in a statement. "Such stem cells can regenerate and replace those damaged cells and tissues and alleviate diseases that affect millions of people."